WO2018048958A1 - Paclitaxel-albumin-binding agent compositions and methods for using and making the same - Google Patents
Paclitaxel-albumin-binding agent compositions and methods for using and making the same Download PDFInfo
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- WO2018048958A1 WO2018048958A1 PCT/US2017/050355 US2017050355W WO2018048958A1 WO 2018048958 A1 WO2018048958 A1 WO 2018048958A1 US 2017050355 W US2017050355 W US 2017050355W WO 2018048958 A1 WO2018048958 A1 WO 2018048958A1
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- nanoparticle
- paclitaxel
- albumin
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Definitions
- This application relates to novel compositions of binding agents and carrier proteins and methods of making and using the same, in particular, as a cancer therapeutic.
- Chemotherapy remains a mainstay for systemic therapy for many types of cancer, including melanoma. Most chemotherapeutic agents are only slightly selective to tumor cells, and toxicity to healthy proliferating cells can be high (Allen TM. (2002) Cancer 2:750- 763), often requiring dose reduction and even discontinuation of treatment.
- one way to overcome chemotherapy toxicity issues as well as improve drug efficacy is to target the chemotherapy drug to the tumor using antibodies that are specific for proteins selectively expressed (or overexpressed) by cancer cells to attract targeted drugs to the tumor, thereby altering the biodistribution of the chemotherapy and resulting in more drug going to the tumor and less affecting healthy tissue.
- specific targeting rarely succeeds in the therapeutic context.
- ADC antibody dependent chemotherapy
- Antibody-targeted chemotherapy promised advantages over conventional therapy because it provides combinations of targeting ability, multiple cytotoxic agents, and improved therapeutic capacity with potentially less toxicity.
- clinically effective antibody -targeted chemotherapy remains elusive: major hurdles include the instability of the linkers between the antibody and chemotherapy drug, reduced tumor toxicity of the chemotherapeutic agent when bound to the antibody, and the inability of the conjugate to bind and enter tumor cells.
- these therapies did not allow for control over the size of the antibody-drug conjugates.
- nanoparticles which contain (a) carrier protein, (b) optionally a binding agent, and (c) paclitaxel, wherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect, and optionally (d) a therapeutic agent.
- Some aspects of the current invention are predicated, in part, on the idea that a reduced amount of paclitaxel, for example compared to that in albumin-bound nanoparticles such as ABRAXA E®, facilitates the formation of a complex of a carrier protein, such as albumin, with a binding agent, such as an antibody, to provide a stable nanoparticle.
- These nanoparticles may be referred to herein as "reduced toxicity nanoparticles” (RTP) or RTP complexes.
- nanoparticles which contain (a) carrier protein, (b) a paclitaxel derivative, the paclitaxel derivative having reduced toxicity compared to paclitaxel, and optionally (c) a binding agent and/or (d) a therapeutic agent.
- nanoparticle compositions and methods of making and using the nanoparticles.
- a nanoparticle comprising albumin and a paclitaxel derivative, wherein the paclitaxel derivative is less toxic than paclitaxel.
- the paclitaxel derivative is a Meerwein Product of Paclitaxel.
- the paclitaxel derivative is 20-acetoxy-4-deactyl-5-epi-20, O-secotaxol.
- the paclitaxel derivative is Baccatin III ((2p,5a,7a, 10a,13P)-4, 10-Diacetoxy-l,7, 13-trihydroxy-9- oxo-5,20-epoxytax-l l-en-2-yl benzoate).
- the nanoparticle is held together by non-covalent bonds between the albumin and the paclitaxel derivative.
- the albumin and the paclitaxel derivative have a relative weight ratio of less than about 10: 1.
- the nanoparticles do not comprise paclitaxel.
- a nanoparticle complex comprising albumin and a paclitaxel derivative, and further comprises binding agents (e.g., antibodies) having an antigen-binding domain.
- binding agents e.g., antibodies
- an amount of the binding agents are arranged on an outside surface of the nanoparticle complexes.
- the binding agents are a substantially single layer of binding agents on all or part of the surface of the nanoparticle.
- the binding agents are bound to the carrier protein by non-covalent bonds.
- the binding agents are antibodies.
- the nanoparticle complex further comprises a therapeutic agent.
- the therapeutic agent is abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vemurafenib, sunitinib
- nanoparticle composition comprising the nanoparticles or nanoparticle complexes as described herein.
- a nanoparticle comprising a carrier protein (e.g., albumin) and paclitaxel, wherein the paclitaxel is is present in an amount that is less than an amount that provides a therapeutic effect.
- the nanoparticle is held together by non-covalent bonds between the carrier protein and the paclitaxel.
- the nanoparticle complex was made by combining the carrier protein (e.g., albumin) and paclitaxel at a relative weight ratio of greater than about 10: 1 carrier protein to paclitaxel.
- the amount of paclitaxel present in the nanoparticles is not limited to the amount of paclitaxel present in the nanoparticles.
- nanoparticle complexes or nanoparticle composition is greater than or equal to a minimum amount capable of providing stability to the nanoparticle complexes comprising a protein carrier (e.g., albumin) and paclitaxel.
- a protein carrier e.g., albumin
- the amount of paclitaxel present in the nanoparticles or nanoparticle composition is greater than or equal to a minimum amount capable of providing affinity of the paclitaxel with the protein carrier (e.g., albumin).
- the amount of paclitaxel present in the nanoparticles or nanoparticle composition is greater than or equal to a minimum amount capable of facilitating complex formation of the paclitaxel and the protein carrier (e.g., albumin).
- the ratio of albumin to paclitaxel in the nanoparticles or nanoparticle composition preferably is less than that present in ABRAXA E®.
- ABRAXA E® contains 100 mg paclitaxel for about 900 mg albumin.
- the weight ratio of the carrier protein (e.g., albumin) to paclitaxel in the nanoparticle composition is greater than about 9: 1.
- the weight ratio is greater than about 10: 1, or 11 : 1, or 12: 1, or 13 : 1, or 14: 1, or 15: 1, or about 16: 1, or about 17: 1, or about 18: 1, or about 19: 1, or about 20: 1, or about 21 : 1 , or about 22 : 1 , or about 23 : 1 , or about 24 : 1 , or about 25 : 1 , or about 26 : 1 , or about 27: 1, or about 28: 1, or about 29: 1, or about 30: 1.
- the weight ratio of the carrier protein to paclitaxel in the nanoparticle complex is greater than about 9: 1.
- the weight ratio is greater than about 10: 1, or 11 : 1, or 12: 1, or 13 : 1, or 14: 1, or 15: 1, or about 16: 1, or about 17: 1, or about 18: 1, or about 19: 1, or about 20: 1, or about 21 : 1, or about 22: 1, or about 23 : 1, or about 24: 1, or about 25: 1, or about 26: 1, or about 27: 1, or about 28: 1, or about 29: 1, or about 30: 1.
- the amount of paclitaxel is greater than or equal to a minimum amount capable of providing stability to the nanoparticle complexes comprising a protein carrier (e.g., albumin) and paclitaxel, and optionally at least one therapeutic agent. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier.
- a protein carrier e.g., albumin
- the amount of paclitaxel can be less than a therapeutic amount for paclitaxel.
- the amount can be less than what is provided or contemplated for providing a therapeutic benefit, such as for example, a chemotherapeutic amount to effectively treat a cancer.
- the amount of paclitaxel present in the nanoparticle composition is less than about 5 mg/mL. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 4.54 mg/mL, or about 4.16 mg/mL, or about 3.57 mg/mL, or about 3.33 mg/mL, or about 3.12 mg/mL, or about 2.94 mg/mL, or about 2.78 mg/mL, or about 2.63 mg/mL, or about 2.5 mg/mL, or about 2.38 mg/mL, or about 2.27 mg/mL, or about 2.17 mg/mL, or about 2.08 mg/mL, or about 2 mg/mL, or about 1.92 mg/mL, or about 1.85 mg/mL, or about 1.78 mg/mL, or about 1.72 mg/mL, or about 1.67 mg/mL.
- binding to the carrier protein occurs through an albumin- binding motif on the binding agents and/or an antibody-binding motif on the carrier protein.
- the binding agent comprises an albumin-binding motif.
- the carrier protein comprises an antibody-binding motif.
- antibody-binding motifs can be found in PCT Application No. PCT/US2017/045643, filed August 4, 2017, which is incorporated herein by reference in its entirety.
- the binding agent is a non-therapeutic and non-endogenous human antibody, a fusion protein, e.g., fusion of an antibody Fc domain to a peptide that binds a target antigen, or an aptamer.
- the binding agent comprises an antigen-binding domain.
- the antigen is CD3, CD19, CD20, CD38, CD30, CD33, CD52, PD-1, PD-L1, PD-L2, CTLA-4, RANK-L, GD-2, Ly6E, HER3, EGFR, DAF, ERBB-3 receptor, CSF-1R, HER2, STEAPl, CD3, CEA, CD40, OX40, Ang2-VEGF, or VEGF.
- the binding agent is an antibody selected from ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, cetuximab, denosumab, dinutuximab, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, Ramucirumab, avelumab or durvalumab, pidilizumab, BMS 936559, OKT3, and trastuzumab.
- ado-trastuzumab emtansine alemtuzumab, atezolizumab, bevacizumab, cetuximab, denosumab, dinutuximab, ipilimumab, nivolumab, obinut
- the invention further includes lyophilized nanoparticles and nanoparticle
- compositions, and lyophilized nanoparticles and compositions that do not materially differ from, or are the same as, the properties of freshly-prepared nanoparticles are similar or identical to the fresh composition in terms of particle size, particle size distribution, toxicity for cancer cells, binding agent affinity, and binding agent specificity.
- lyophilized nanoparticles retain the properties of freshly-made nanoparticles after resuspension, notwithstanding the presence of two different protein components in these particles.
- the lyophilized composition is stable at room temperature for at least about 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the lyophilized composition is stable at room temperature for at least 3 months.
- the reconstituted nanoparticles retain the activity of the therapeutic agent and are capable of binding to the target in vivo. [0023] In some embodiments, the at least one therapeutic agent is located inside the nanoparticle. In other embodiments, the at least one therapeutic agent is located on the outside surface of the nanoparticle. In yet other embodiments, the at least one therapeutic agent is located inside the nanoparticle and on the outside surface of the nanoparticle.
- the nanoparticle contains more than one type of therapeutic agent.
- a taxane and a platinum drug e.g. paclitaxel and cisplatin.
- the nanoparticle further comprises at least one additional therapeutic agent that is not paclitaxel.
- the at least one therapeutic agent is abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vemurafen
- the binding agents, carrier protein and/or, when present, therapeutic agent are bound through non-covalent bonds.
- the carrier protein is selected from the group consisting of gelatin, elastin, gliadin, legumin, zein, a soy protein, a milk protein, and a whey protein.
- the carrier protein is albumin, for example, human serum albumin.
- the composition is formulated for intravenous delivery. In other embodiments, the composition is formulated for direct injection or perfusion into a tumor.
- the nanoparticles have a dissociation constant between about 1 x 10 "11 M and about 1 x 10 "9 M.
- provided herein are methods of making the nanoparticle compositions, wherein said method comprises contacting the carrier protein and the paclitaxel and the at least one therapeutic agent under conditions and ratios of components that will allow for formation of the desired nanoparticles.
- methods for forming an albumin-paclitaxel derivative or albumin-paclitaxel nanoparticle wherein method comprises: homogenizing the albumin with paclitaxel derivative or paclitaxel in a solution under high pressure, to generate an albumin-paclitaxel derivative or albumin-paclitaxel nanoparticle.
- nanoparticle compositions comprising contacting the carrier protein, the paclitaxel, and/or the therapeutic agent with the binding agents in a solution having a pH of between 5.0 and 7.5 and a temperature between about 5°C and about 60°C, between about 23°C and about 60°C, or between about 55°C and about 60°C under conditions and ratios of components that will allow for formation of the desired nanoparticles.
- the nanoparticle is made between 55°C and 60°C and pH 7.0.
- nanoparticle compositions comprising (a) contacting the carrier protein, the paclitaxel and the therapeutic agent to form a core and (b) optionally contacting the core with the antibodies in a solution having a pH of about 5.0 to about 7.5 at a temperature between about 5°C and about 60°C, between about 23°C and about 60°C, or between about 55°C and about 60°C under conditions and ratios of components that will allow for formation of the desired nanoparticles.
- an amount of a therapeutic agent can also be added to the carrier protein.
- the nanoparticles are made as above, and then lyophilized.
- methods for treating a cancer cell comprising contacting the cell with an effective amount of a nanoparticle composition disclosed herein to treat the cancer cell.
- a method for killing cancer cells in a population of cancer cells comprising contacting the cells with an effective amount of a nanoparticle composition, wherein said composition is maintained in contact with said cells for a sufficient period of time to kill cancer cells, wherein said nanoparticle composition comprises nanoparticle complexes, each of the nanoparticles comprising albumin and paclitaxel,wherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect.
- a method for treating cancer in patient in need thereof comprising administering to the patient a nanoparticle composition comprising nanoparticle complexes, each of the nanoparticles comprising albumin and paclitaxel,wherein the paclitaxel is present in an amount that is less than an amount that provides a therapeutic effect.
- a tumor in a patient in need thereof comprising contacting the cell with an effective amount of a nanoparticle composition disclosed herein to treat the tumor.
- the size of the tumor is reduced.
- the nanoparticle composition is administered intravenously.
- the nanoparticle composition is administered by direct injection or perfusion into the tumor.
- the methods provided herein include the steps of: a) administering the nanoparticle composition once a week for three weeks; b) ceasing administration of the nanoparticle composition for one week; and c) repeating steps a) and b) as necessary to treat the tumor.
- the therapeutically effective amount comprises about 75 mg/m 2 to about 175 mg/m 2 of the carrier protein (i.e., milligrams carrier protein per m 2 of the patient).
- the paclitaxel is of an amount that is less than about 75 mg/m 2 , such as between 5 mg/m 2 and 75 mg/m 2 .
- the paclitaxel is of an amount that is less than a therapeutically effective amount.
- the therapeutic agent is of a therapeutically effective amount.
- the therapeutically effective amount comprises about 30 mg/m 2 to about 70 mg/m 2 of the binding agent.
- the therapeutically effective amount comprises about 30 mg/m 2 to about 70 mg/m 2 bevacizumab.
- An embodiment of the invention includes a method for increasing the duration of tumor uptake of a chemotherapeutic agent by administering the chemotherapeutic agent in a nanoparticle comprising a carrier protein and the chemotherapeutic agent having surface complexation with an antibody, e.g., an antibody that specifically binds to an antigen on or shed by the tumor.
- an antibody e.g., an antibody that specifically binds to an antigen on or shed by the tumor.
- ABRAXA E® and bevacizumab employ the acronym " AB” and the number after AB such as AB 160 is meant to confer the average particle size of these nanoparticles (in nanometers).
- the acronym is "AR” while the number thereafter remains the same.
- FIG. 1 shows the reaction of paclitaxel with Meerwein's Reagent to form the Meerwein's Product of Paclitaxel (20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol).
- FIGs. 2A-2E show the nanoparticle diameter of non-toxic nanoparticles (NTP) alone (FIG. 2A) or incubated with 4 mg/mL (FIG. 2B), 6 mg/mL (FIG 2C), 8 mg/mL (FIG. 2D) or 10 mg/mL (FIG. 2E) bevacizumab for 30 min. Diameter was measured at a 1 :300 dilution using Malvern Nanosight technology.
- FIGs. 3A and 3B show the binding affinity (Kd) of bevacizumab (FIG. 3 A) or rituximab (FIG. 3B) to NTP. Kd was measured using Bio Layer Interferometry Technology.
- FIG. 4A shows the stability of nanoparticle complexes in PBS.
- FIG. 4B shows the stability of nanoparticle complexes in serum.
- FIGs. 5A-5E show blocking of CD20-positive Daudi cells with isotype control (FIG. 5 A), anti-CD20 antibody (FIG. 5B), ABRAXANE® (FIG. 5C), AR160 (FIG. 5D), NTP (FIG. 5E), rituximab-bound NTP (NTRit; FIG. 5F), or rituximab alone (FIG. 5G).
- the term "about” when used with regard to a dose amount means that the dose may vary by +/- 10%.
- “about 400 to about 800 binding agents” indicates that an outside surface of a nanoparticles contain an amount of binding agent between 360 and 880 particles.
- compositions and methods include the recited elements, but not excluding others.
- Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
- Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
- nanoparticle refers to particles having at least one dimension which is less than 5 microns. In preferred embodiments, such as for intravenous administration, the nanoparticle is less than 1 micron. For direct administration, the nanoparticle is larger. Even larger particles are expressly contemplated by the invention.
- D50 is the particle size below which 50% of the particles fall. 10% of particles are smaller than the D10 value and 90% of particles are smaller than D90. Where unclear, the "average" size is equivalent to D50. So, for example, AB 160 and AR160 refer to nanoparticles having an average size of 160 nanometers.
- nanoparticle may also encompass discrete multimers of smaller unit nanoparticles. For 160 nm nanoparticles, multimers would therefore be approximately 320 nm, 480 nm, 640 nm, 800 nm, 960 nm, 1 120 nm, and so on.
- carrier protein refers to proteins that function to transport binding agents and/or therapeutic agents.
- the binding agents of the present disclosure can reversibly bind to the carrier proteins. Examples of carrier proteins are discussed in more detail below.
- core refers to a central or inner portion of the nanoparticle which may be comprised of a carrier protein, a carrier protein and a therapeutic agent, or other agents or combination of agents.
- an albumin-binding motif of the binding agent may be associated with the core.
- therapeutic agent means an agent which is therapeutically useful, e.g., an agent for the treatment, remission or attenuation of a disease state, physiological condition, symptoms, or etiological factors, or for the evaluation or diagnosis thereof.
- a therapeutic agent may be a chemotherapeutic agent, for example, mitotic inhibitors, topoisomerase inhibitors, steroids, anti-tumor antibiotics, antimetabolites, alkylating agents, enzymes, proteasome inhibitors, or any combination thereof.
- binding agent refers to an agent that binds to a target antigen and does not significantly bind to unrelated compounds.
- binding agents that can be effectively employed in the disclosed methods include, but are not limited to, lectins, proteins, and antibodies, such as monoclonal antibodies, e.g. humanized monoclonal antibodies, chimeric antibodies, or polyclonal antibodies, or antigen-binding fragments thereof, as well as aptamers, fusion proteins, and aptamers having or fused to an albumin- binding motif.
- the binding agent is an exogenous antibody.
- An exogenous antibody is an antibody not naturally produced in a mammal, e.g. in a human, by the mammalian immune system.
- antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules (i.e., molecules that contain an antigen binding site that immuno-specifically bind an antigen).
- the term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and portions thereof; including, for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR- grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, a functionally active epitope-binding fragment thereof, bifunctional hybrid antibodies (e.g., Lanzavecchia et al, Eur.
- the antibody may be of any type (e.g., IgG, IgA, IgM, IgE or IgD).
- the antibody is IgG.
- An antibody may be non-human (e.g., from mouse, goat, or any other animal), fully human, humanized, or chimeric.
- Antibody or antibodies include any biosimilar(s) of the antibodies disclosed herein. Biosimilars, as used herein, refers to a biopharmaceutical which is deemed to be comparable in quality, safety, and efficacy to a reference product marketed by an innovator company (Section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)).
- dissociation constant also referred to as "K4,” refers to a quantity expressing the extent to which a particular substance separates into individual components (e.g., the protein carrier, antibody, and a therapeutic agent).
- lyophilized refers to a process by which the material (e.g., nanoparticles) to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment.
- An excipient is optionally included in pre-lyophilized formulations to enhance stability of the lyophilized product upon storage.
- the nanoparticles can be formed from lyophilized components (carrier protein, paclitaxel, and optionally antibody and/or a therapeutic agent) prior to use as a therapeutic.
- the carrier protein and paclitaxel, and optionally a binding agent, e.g., antibody, and/or a therapeutic agent are first combined to facilitate the formation of stable nanoparticles and then lyophilized.
- the lyophilized sample may further contain additional excipients.
- the term "bulking agents" comprise agents that provide the structure of the fireeze- dried product. Common examples used for bulking agents include mannitol, glycine, lactose and sucrose. In addition to providing a pharmaceutically elegant cake, bulking agents may also impart useful qualities in regard to modifying the collapse temperature, providing fireeze- thaw protection, and enhancing the protein stability over long-term storage. These agents can also serve as tonicity modifiers.
- the lyophilized compositions described herein comprise bulking agents. In some embodiments, the lyophilized
- compositions described herein do not comprise bulking agents.
- buffer encompasses those agents which maintain the solution pH in an acceptable range prior to lyophilization and may include succinate (sodium or potassium), histidine, phosphate (sodium or potassium), Tris(tris(hydroxymethyl)aminomethane), diethanolamine, citrate (sodium) and the like.
- the buffer of this invention may have a pH in the range from about 5.5 to about 6.5; and preferably has a pH of about 6.0. Examples of buffers that will control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
- cryoprotectants generally includes agents which provide stability to the protein against freezing-induced stresses, presumably by being preferentially excluded from the protein surface. They may also offer protection during primary and secondary drying, and long-term product storage. Examples are polymers such as dextran and polyethylene glycol; sugars such as sucrose, glucose, trehalose, and lactose; surfactants such as
- polysorbates polysorbates; and amino acids such as glycine, arginine, and serine.
- lyoprotectant includes agents that provide stability to the protein during the drying or 'dehydration' process (primary and secondary drying cycles), presumably by providing an amorphous glassy matrix and by binding with the protein through hydrogen bonding, replacing the water molecules that are removed during the drying process. This helps to maintain the protein conformation, minimize protein degradation during the lyophilization cycle and improve the long-term products.
- examples include polyols or sugars such as sucrose and trehalose.
- composition refers to preparations which are in such form as to permit the active ingredients to be effective, and which contains no additional components that are toxic to the subjects to which the formulation would be administered.
- “Pharmaceutically acceptable” excipients are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
- Reconstitution time is the time that is required to rehydrate a lyophilized formulation into a solution.
- a “stable" formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage.
- various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period.
- epitope refers to the portion of an antigen which is recognized by a binding agent, e.g., an antibody.
- a binding agent e.g., an antibody.
- Epitopes include, but are not limited to, a short amino acid sequence or peptide (optionally glycosylated or otherwise modified) enabling a specific interaction with a protein (e.g., an antibody) or ligand.
- a protein e.g., an antibody
- ligand e.g., an antibody
- an epitope may be a part of a molecule to which the antigen-binding site of a binding agent attaches.
- treating covers the treatment of a disease or disorder (e.g., cancer), in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disease or disorder; (iii) slowing progression of the disease or disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
- treating refers to the killing of cancer cells.
- the term "kill” or “killing” with respect to a cancer treatment includes any type of manipulation that will directly or indirectly lead to the death of that cancer cell or at least of portion of a population of cancer cells.
- aptamer refers to a nucleic acid molecule that is capable of binding to a target molecule, such as a polypeptide.
- a target molecule such as a polypeptide.
- an aptamer of the invention can specifically bind to e.g., CD20, CD38, CD52, PD-1, PD-L1, PD-L2, Ly6E, HER2,
- HER3/EGFR DAF ERBB-3 receptor
- CSF-1R CSF-1R
- STEAP1 CD3, CEA, CD40, OX40, Ang2- VEGF, and VEGF.
- the generation of antibodies with a particular binding specificity and the therapeutic use of aptamers are well established in the art. See, e.g., U.S. Pat. No. 5,475,096, U.S. Pat. Nos. 5,270, 163, 5,582,981, 5,840,867, 6,011,020, 6,051,698, 6,147,204, 6,180,348 and 6,699,843, and the therapeutic efficacy of Macugen® (Eyetech, New York) for treating age-related macular degeneration, each of which is incorporated herein by reference in its entirety.
- oligomer or "oligomeric” or “oligomerized” as used herein refers to oligomers composed of two or more monomers.
- Fusion proteins are bioengineered polypeptides that join a protein or fragment thereof (e.g., the crystallizable fragment (Fc) domain of an antibody) with another biologically active agent (e.g., a protein domain, peptide, or nucleic acid or peptide aptamer) to generate a molecule with desired structure-function properties and significant therapeutic potential.
- a protein or fragment thereof e.g., the crystallizable fragment (Fc) domain of an antibody
- another biologically active agent e.g., a protein domain, peptide, or nucleic acid or peptide aptamer
- IgG immunoglobulin
- non-toxic nanoparticles or “NTP complexes” refers to nanoparticles comprising a carrier protein (e.g., albumin) and a paclitaxel derivative that is less toxic than paclitaxel.
- the NTPs or NTP complexes comprise binding agents (e.g., antibodies) and/or therapeutic agents (e.g., chemotherapeutic agents).
- the phrase "less toxic than paclitaxel” refers to paclitaxel derivatives that exhibit reduced toxicity to (e.g., reduced killing of) cells, including cancer cells and normal cells, as compared to paclitaxel.
- the Meerwein Product of Paclitaxel (20-Acetoxy-4- deactyl-5-epi-20, O-secotaxol) has significantly reduced toxicity, likely due to the breaking of the C-4,C-5 oxetane ring of paclitaxel.
- RTPs reduced toxicity nanoparticles
- RTP complexes refers to nanoparticles comprising a carrier protein (e.g., albumin) and a reduced amount of paclitaxel compared to ABRAXANE® (.g., an albumin: paclitaxel ratio of about 9: 1).
- the RTPs or RTP complexes comprise binding agents (e.g., antibodies) and/or therapeutic agents (e.g., chemotherapeutic agents).
- ABRAXANE® for Injectable Suspension is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel can exist in the particles in a non-crystalline, amorphous state.
- ABRAXANE® can be supplied as, for example, a lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion.
- a single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.
- ABRAXANE® nanoparticles are stabilized albumin-bound paclitaxel.
- the association of the paclitaxel and albumin can be via, for example, hydrophobic interactions.
- the nanoparticle are stable at an average size of 130 nm. It is also known that other hydrophobic drugs such as, for example, docetaxel, rapamycin, can similarly form stabilized nanoparticles by binding to albumin.
- ADCs Another shortcoming of current ADCs is that higher drug penetration into the tumor has not been substantively proven in human tumors.
- Early testing of ADCs in mouse models suggested that tumor targeting with antibodies would result in a higher concentration of the active agent in the tumor (Deguchi, T. et al. (1986) Cancer Res 46: 3751-3755); however, this has not correlated in the treatment of human disease, likely because human tumors are much more heterogeneous in permeability than mouse tumors. Jain, R.K. et al. (2010) Nat Rev Clin Oncol 7:653-664. Also, the size of the nanoparticle is critical for extravasation from the vasculature into the tumor.
- the nano-immune conjugate described herein overcomes this issue by the fact that the large complex, which is less than 200 nm intact, is partially dissociated in systemic circulation into smaller functional units that are easily able to permeate tumor tissue. Furthermore, once the conjugate arrives to the tumor site, the smaller toxic payload can be released and only the toxic portion needs to be taken up by tumor cells, not the entire conjugate.
- RTP reduced toxicity nanoparticles
- a carrier protein e.g., albumin
- paclitaxel e.g., compared to ABRAXA E®
- NTP non-toxic nanoparticles
- the nanoparticles may further include a therapeutic agent and/or binding agents (e.g., antibodies).
- the present disclosure relates to nanoparticles and compositions of nanoparticles containing a carrier protein (e.g., albumin) and a paclitaxel derivative (e.g., a derivative that is less toxic than paclitaxel) or a reduced amount of paclitaxel (e.g., compared to a therapeutic amount, and/or compared to an amount in ABRAXANE®).
- a carrier protein e.g., albumin
- a paclitaxel derivative e.g., a derivative that is less toxic than paclitaxel
- a reduced amount of paclitaxel e.g., compared to a therapeutic amount, and/or compared to an amount in ABRAXANE®.
- the nanoparticles also contain binding agents and/or a therapeutic agent.
- the nanoparticles or nanoparticle composition is lyophilized.
- the present invention is further predicated, in part, on the formation of nanoparticles comprising a carrier protein and paclitaxel in a lower amount than is present in
- paclitaxel e.g., to cells
- a binding agent and/or a therapeutic agent e.g., to cells
- such nanoparticles provide targeted therapy to a tumor while minimizing toxicity to the patient, and can be used to treat tumors that traditionally are not susceptible to paclitaxel and/or that respond better to a different therapeutic agent.
- the carrier protein can be albumin, gelatin, elastin (including topoelastin) or elastin-derived polypeptides (e.g., a-elastin and elastin-like polypeptides (ELPs)), gliadin, legumin, zein, soy protein (e.g., soy protein isolate (SPI)), milk protein (e.g., ⁇ -lactoglobulin (BLG) and casein), or whey protein (e.g., whey protein concentrates (WPC) and whey protein isolates (WPI)).
- the carrier protein is albumin.
- the albumin is egg white (ovalbumin), bovine serum albumin (BSA), or the like.
- the carrier protein is human serum albumin (HSA).
- the carrier protein is a recombinant protein (e.g., recombinant HSA).
- the carrier protein is a generally regarded as safe (GRAS) excipient approved by the United States Food and Drug Administration (FDA).
- the binding agents are antibodies selected from ado- trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, cetuximab, denosumab, dinutuximab, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, avelumab or durvalumab, pidilizumab, BMS 936559, and trastuzumab.
- the antibodies are selected from the antibodies listed in Table 1.
- the antibodies are a substantially single layer of antibodies on all or part of the surface of the nanoparticle.
- Table 1 depicts a list of non-limiting list of antibodies.
- Blinatumomab (Blincyto) Acute lymphocytic leukemia (ALL)
- Pembrolizumab Keytruda®
- PD-1 melanoma, non-small cell lung cancer
- Nivolumab (Opdivo®) PD-1 (melanoma, non-small cell lung cancer)
- DLBCL diffuse large B-cell lymphoma
- Obinutuzumab (Gazyva®) indolent NHL (lst-line)
- BioCentury BCIQ Acute myelogenous leukemia (AML)
- DLBCL drug conjugate
- NHL bladder cancer NSCLC
- melanoma breast, renal cell
- RG7446 anti-PD-Ll mAb carcinoma, lymphoma
- Atezolizumab (Tecentriq®, anti- PD-Ll) Bladder cancer, metastatic NSCLC
- RG7221 (Ang2-VEGF mAb) Metastatic colorectal cancer
- RG7686 (glypican-3 mAb) Hepatocellular carcinoma
- NSCLC head and neck, bladder, gastric, pancreatic, HCC
- the at least one therapeutic agent is selected from abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, soraf
- Table 2 depicts a list of non-limiting list of cancer therapeutic agents.
- the therapeutic agent is selected from the agents recited in Table 2.
- Aromasin (Exemestane) Advanced breast cancer Advanced breast cancer; early-stage breast cancer and estrogen receptor positive
- Arranon (Nelarabine) T-cell acute lymphoblastic leukemia; T-cell lymphoblastic lymphoma
- BiCNU Carmustine Brain tumors; Hodgkin lymphoma; multiple myeloma; non-Hodgkin lymphoma
- penile cancer squamous cell carcinoma of the cervix; squamous cell carcinoma of the head and neck; squamous cell carcinoma of the vulva; testicular cancer
- Clofarex (Clofarabine) Acute lymphoblastic leukemia
- Cosmegen (Dactinomycin) Ewing sarcoma; gestational trophoblastic disease; rhabdomyosarcoma; solid tumors; testicular cancer; Wilms tumor
- Cytoxan or Neosar Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma;
- mycosis fungoides neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;
- Denosumab Giant cell tumor of the bone breast cancer, prostate cancer
- DTIC-Dome Hodgkin lymphoma; melanoma
- Eloxatin (Oxaliplatin) Colorectal cancer; stage III colon cancer
- Emend (Aprepitant) Nausea and vomiting caused by chemotherapy and nausea and vomiting after surgery
- Erbitux Colorectal cancer; squamous cell carcinoma of the head and neck
- Etopophos Small cell lung cancer; testicular cancer
- Fludara (Fludarabine Phosphate) Chronic lymphocytic leukemia
- FU-LV Colorectal cancer esophageal cancer
- gastric cancer esophageal cancer
- GEMCITABINE-CISPLATIN Biliary tract cancer bladder cancer; cervical cancer; malignant mesothelioma; non-small cell lung cancer; ovarian cancer; pancreatic cancer
- Gemzar (Gemcitabine Hydrochloride) Breast cancer; non-small cell lung cancer;
- pancreatic cancer ovarian cancer; pancreatic cancer
- Gleevec (Imatinib Mesylate) Acute lymphoblastic leukemia; chronic myeloblastic leukemia
- eosinophilic leukemia or hypereosinophilic syndrome eosinophilic leukemia or hypereosinophilic syndrome
- chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
- dermatofibrosarcoma protuberans eosinophilic leukemia or hypereosinophilic syndrome
- chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
- chronic myelogenous leukemia dermatofibrosarcoma protuberans
- myelodysplastic/myeloproliferative neoplasms myelodysplastic/myeloproliferative neoplasms; systemic mastocytosis.
- Gliadel Carmustine Implant
- Glioblastoma multiforme malignant glioma
- Hycamtin Topotecan Hydrochloride Cervical cancer; ovarian cancer; small cell lung cancer
- Hyper-CVAD Acute lymphoblastic leukemia; non-Hodgkin lymphoma
- Iclusig Ponatinib Hydrochloride
- Idamycin (Idarubicin Hydrochloride) Acute myeloid leukemia
- Imbruvica (Ibrutinib) Chronic lymphocytic leukemia; mantle cell lymphoma; Waldenstr6m macroglobulinemia
- Mitozytrex (Mitomycin C) Gastric (stomach) and
- Mustargen (Mechlorethamine Hydrochloride) Bronchogenic carcinoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; mycosis fungoides; non-Hodgkin lymphoma
- Mylotarg (Gemtuzumab Ozogamicin) Acute myeloid leukemia Navelbine (Vinorelbine Tartrate)
- Nolvadex (Tamoxifen Citrate) Breast cancer
- Non-small cell lung cancer Ovarian cancer
- Platinol (Cisplatin) Bladder cancer Cervical cancer; Malignant mesothelioma; Non-small cell lung cancer; Ovarian cancer; Squamous cell carcinoma of the head and neck; Testicular cancer
- Prednisone Acute lymphoblastic leukemia; Chronic lymphocytic leukemia; Hodgkin lymphoma; Multiple myeloma; Non-Hodgkin lymphoma; Prostate cancer; Thymoma and thymic carcmoma
- Purinethol Acute lymphoblastic leukemia
- Anemia Rubidomycin (Daunorubicin Hydrochloride) Acute lymphoblastic leukemia; Acute myeloid leukemia
- Somatuline Depot (Lanreotide Acetate) Gastroenteropancreatic neuroendocrine tumors
- Sutent Gastronintestinal stromal tumor; Pancreatic cancer; Renal cell carcinoma
- Tarabine PFS Cytarabine Acute lymphoblastic leukemia; Acute myeloid leukemia; Chronic myelogenous leukemia; meningeal leukemia
- Tasigna Chronic myelogenous leukemia
- Taxol (Paclitaxel) AIDS-related Kaposi sarcoma; Breast cancer;
- Non-small cell lung cancer Ovarian cancer
- Taxotere Docetaxel Breast cancer; Adenocarcinoma; Non-small cell lung cancer; Prostate cancer; Squamous cell carcinoma of the head and neck;
- Temodar or Methazolastone Anaplastic astrocytoma; Glioblastoma
- Thiotepa Bladder cancer Breast cancer; Malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; Ovarian cancer Toposar or VePesid (Etoposide) Small cell lung cancer; Testicular cancer
- Torisel (Temsirolimus) Renal cell carcinoma
- TPF Squamous cell carcinoma of the head and neck; Gastric (stomach) cancer
- Treanda Bendamustine Hydrochloride B-cell non-Hodgkin lymphoma; Chronic lymphocytic leukemia
- Trisenox Arsenic Trioxide Acute promyelocytic leukemia
- Velsar or Velban (Vinblastine Sulfate) Breast cancer; Choriocarcinoma; Hodgkin lymphoma; Kaposi sarcoma; Mycosis fungoides; Non-Hodgkin lymphoma;
- Vincasar PFS Vincristine Sulfate Acute leukemia; Hodgkin lymphoma;
- Neuroblastoma Non-Hodgkin lymphoma; Rhabdomyosarcoma; Wilms tumor
- Zydelig Chronic lymphocytic leukemia; Non-Hodgkin lymphoma (Follicula B-cell non Hodgkin lymphoma and Small lymphocytic lymphoma)
- the therapeutic agent may be located inside the body
- nanoparticle on the outside surface of the nanoparticle, or both.
- the nanoparticle may contain more than one therapeutic agent, for example, two therapeutic agents, three therapeutic agents, four therapeutic agents, five therapeutic agents, or more.
- a nanoparticle may contain the same or different therapeutic agents inside and outside the nanoparticle.
- the nanoparticle comprises at least 100 binding agents non-covalently bound to the surface of the nanoparticle. In one aspect, the nanoparticle comprises at least 200, 300, 400, 500, 600, 700 or 800 binding agents non-covalently bound to the surface of the nanoparticle.
- the nanoparticle comprises between about 100 and about 1000 binding agents non-covalently bound to the surface of the nanoparticle. In one aspect, the nanoparticle comprises between about 200 and about 1000, between about 300 and about 1000, between about 400 and about 1000, between about 500 and about 1000, between about 600 and about 1000, between about 200 and about 800, between about 300 and about 800, or between about 400 and about 800 binding agents non-covalently bound to the surface of the nanoparticle.
- Contemplated values include any value or subrange within any of the recited ranges, including endpoints.
- the average particle size in the nanoparticle composition is less than about 1 pm. In one aspect, the average particle size in the nanoparticle composition is between about 50 nm and about 1 pm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 900 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 800 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 700 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 600 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 500 nm.
- the average particle size in the nanoparticle composition is between about 60 nm and about 400 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 300 nm. In one aspect, the average particle size in the nanoparticle composition is between about 60 nm and about 200 nm. In one aspect, the average particle size in the nanoparticle composition is between about 80 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm.
- the average particle size in the nanoparticle composition is between about 100 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. In one aspect, the average particle size in the nanoparticle composition is between about 120 nm and about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints.
- the nanoparticle composition is formulated for intravenous injection.
- the nanoparticle composition formulated for intravenous injection should comprise nanoparticles with an average particle size of less than about 1 ⁇ .
- the average particle size in the nanoparticle composition is greater than about 1 ⁇ . In one aspect, the average particle size in the nanoparticle composition is between about 1 ⁇ and about 5 ⁇ , between about 1 ⁇ and about 4 ⁇ , between about 1 ⁇ and about 3 ⁇ , between about 1 ⁇ and about 2 ⁇ , or between about 1 ⁇ and about 1.5 ⁇ . Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints.
- the nanoparticle composition is formulated for direct injection into a tumor.
- Direct injection includes injection into or proximal to a tumor site, perfusion into a tumor, and the like.
- the nanoparticle may comprise any average particle size. Without being bound by theory, it is believed that larger particles (e.g., greater than 500 nm, greater than 1 ⁇ , and the like) are more likely to be immobilized within the tumor, thereby providing a beneficial effect. Larger particles can accumulate in the tumor or specific organs. See, e.g., 20-60 micron glass particle that is used to inject into the hepatic artery feeding a tumor of the liver, called "THERASPHERE®" (in clinical use for liver cancer). Therefore, for intravenous administration, particles under 1 ⁇ are typically used. Particles over 1 ⁇ are, more typically, administered directly into a tumor (“direct injection”) or into an artery feeding into the site of the tumor.
- less than about 0.01% of the nanoparticles within the composition have a particle size greater than 200 nm, greater than 300 nm, greater than 400 nm, greater than 500 nm, greater than 600 nm, greater than 700 nm, or greater than 800 nm. In one aspect, less than about 0.001% of the nanoparticles within the composition have a particle size greater than 200 nm, greater than 300 nm, greater than 400 nm, greater than 500 nm, greater than 600 nm, greater than 700 nm, or greater than 800 nm. In a preferred embodiment, less than about 0.01% of the nanoparticles within the composition have a particle size greater than 800 nm. In a more preferred embodiment, less than about 0.001%) of the nanoparticles within the composition have a particle size greater than 800 nm.
- the sizes and size ranges recited herein relate to particle sizes of the reconstituted lyophilized nanoparticle composition. That is, after the lyophilized nanoparticles are resuspended in an aqueous solution (e.g., water, other pharmaceutically acceptable excipient, buffer, etc.), the particle size or average particle size is within the range recited herein.
- an aqueous solution e.g., water, other pharmaceutically acceptable excipient, buffer, etc.
- At least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%), or 99.9%) of the nanoparticles are present in the reconstituted composition as single nanoparticles. That is, fewer than about 50%, 40%, 30%, etc. of the nanoparticles are dimerized or multimerized (oligomerized).
- the nanoparticles in the composition have less than 20% by number dimerization, less than 10% by number dimerization and preferably less than 5% dimerization.
- the size of the nanoparticle can be controlled by the adjusting the amount (e.g., ratio) of carrier protein to paclitaxel or paclitaxel derivative, and/or ratio of carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles to binding agent.
- the size of the nanoparticles, and the size distribution, is also important.
- the nanoparticles of the invention may behave differently according to their size. At large sizes, an agglomeration may block blood vessels. Therefore, agglomeration of nanoparticles can affect the performance and safety of the composition. On the other hand, larger particles may be more therapeutic under certain conditions (e.g., when not administered intravenously).
- Further challenges are imposed because the nanoparticles are used in therapy.
- the size of nanoparticles, and the distribution of the size, is also important.
- Nanoparticles may behave differently according to their size. At large sizes, nanoparticles or the agglomeration of the particles may block blood vessels either of which can affect the performance and safety of the composition.
- Paclitaxel derivatives used in the present invention preferably are less toxic than paclitaxel. That is, the paclitaxel derivative is less toxic to cells (e.g., does not kill cancer and/or normal cells as well as, or does not inhibit cell proliferation as well as) compared to paclitaxel. Paclitaxel derivatives may include any derivative or precursor of paclitaxel.
- Examples include, but are not limited to, 20-Acetoxy-4-deactyl-5-epi-20, O-secotaxol (the Meerwein Product of Paclitaxel), or Baccatin III ((2p,5a,7a,10a, 13P)-4, 10-Diacetoxy-l,7, 13- trihydroxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate).
- paclitaxel derivatives and derivatives of different stereochemistry demonstrated reduced activity in comparison to paclitaxel.
- the 2'- hydroxyl and the 3'-benzamido group are not essential for bioactivity, but are important for strong microtubule binding and cytotoxicity.
- Formation of ethers at 2'-hydroxyl group such as alkyl ether (e.g., methyl ether) and alkyl silyl ether (e.g., ter-butyldimethylsilyl ether), reduced cytotoxicity.
- alkyl ether e.g., methyl ether
- alkyl silyl ether e.g., ter-butyldimethylsilyl ether
- Acylation of the 2'- hydroxyl group e.g., 2'-acetyltaxol
- halogen e.g, fluorine
- Lead tetracetate oxidation of 6a-hydroxy-7-epi- paclitaxel leads to C-nor-paclitaxel and C-seco-paclitaxel derivatives.
- Tetrapropylammonium perruthenate (TPAP) oxidation of a 6a-hydroxy-7-epi-paclitaxel derivative leads to a 6- formyl-C-nor-paclitaxel derivative.
- paclitaxel derivative may include modifications at any one or more of these sites or produced by one or more of these methods. See, e.g., Liang et al. Tetrahedron, 53(10):3441- 3456 (1997); US 5,756,301; US 5,981,777; each of which is incorporated by reference herein in its entirety.
- the current invention relates to methods of making nanoparticle compositions as described herein.
- this disclosure relates to methods of making the nanoparticle compositions, wherein said method comprises contacting the carrier protein and the paclitaxel or paclitaxel derivative under conditions and ratios of components that will allow for formation of the desired nanoparticles.
- the methods further relate to contacting a nanoparticle with binding agents and/or therapeutic agent under conditions to form nanoparticle complexes.
- the nanoparticles are made by combining the carrier protein and paclitaxel or paclitaxel derivative, and homogenizing under high pressure to form stable nanoparticles.
- homogenizing albumin and taxane e.g., paclitaxel
- Non-limiting methods for homogenizing albumin and taxane can be found, for example, in Example 1, as well as U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579, each of which is incorporated herein by reference in its entirety.
- binding agents and/or therapeutic agents are complexed to the nanoparticles as described, for example, in U.S. Patent Nos. 9,757,453; and 9,446, 148.
- nanoparticle complexes comprising contacting the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticle with the binding agents and/or therapeutic agent in a solution having a pH of between 5.0 and 7.5 and a temperature between about 5 °C and about 60 °C, between about 23 °C and about 60 °C, or between about 55 °C and about 60 °C under conditions and ratios of components that will allow for formation of the desired nanoparticles.
- the nanoparticle is made at 55- 60 °C and pH 7.0.
- nanoparticle complexes comprising (a) homogenizing the carrier protein and paclitaxel (or paclitaxel derivative) to form a nanoparticle core; and (b) contacting the core with the antibodies in a solution having a pH of about 5.0 to about 7.5 at a temperature between about 5°C and about 60°C, between about 23°C and about 60°C, or between about 55°C and about 60°C under conditions and ratios of components that will allow for formation of the desired nanoparticle complexes.
- Another embodiment of the invention includes a method for making a nanoparticle composition by facilitating complex formation of a protein carrier and a therapeutic agent, the method comprising contacting the carrier protein, an amount of paclitaxel as described herein, and a therapeutic agent in a solution having a pH of 5.0 or greater and a temperature between about 5°C and about 60°C, to generate a nanoparticle.
- the method further comprises contacting the protein-carrier complex with a binding agent.
- the amount of components e.g., carrier protein, antibodies, paclitaxel or paclitaxel derivative, therapeutic agents, combinations thereof
- the amount of components is controlled in order to provide for formation of the desired nanoparticles.
- a composition wherein the amount of components is too dilute will not form the nanoparticles as described herein.
- An overly concentrated solution will result in unstructured aggregates.
- weight ratio of carrier protein to binding agent is 10:4.
- the amount of carrier protein is between about 1 mg/mL and about 100 mg/mL.
- the amount of binding agent is between about 1 mg/mL and about 30 mg/mL.
- the ratio of carrier protein: binding agent: solution is approximately 9 mg of carrier protein (e.g., albumin) to 4 mg of binding agent (e.g., BEV) in 1 mL of solution (e.g., saline).
- the amount of solution or other liquid medium employed to form the nanoparticles is particularly important.
- the amount of solution e.g., sterile water, saline, phosphate buffered saline
- the amount of solution employed is between about 0.5 mL of solution to about 20 mL of solution.
- the nanoparticle complexes of the nanoparticle composition are formed by contacting the carrier protein-paclitaxel (opr paclitaxel derivative) nanoparticles and at least one therapeutic agent with the binding agent at a ratio of about 10: 1 to about 10:30 carrier protein particle or carrier protein-therapeutic agent particle to binding agent.
- the ratio is about 10:2 to about 10:25.
- the ratio is about 10:2 to about 1 : 1.
- the ratio is about 10:2 to about 10:6.
- the ratio is about 10:4.
- Contemplated ratios include any value, subrange, or range within any of the recited ranges, including endpoints.
- the nanoparticles of the nanoparticle composition are formed by contacting the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles and at least one therapeutic agent.
- the ratio is about 10:2 to about 10:25. In one embodiment, the ratio is about 10:2 to about 1 : 1. In a preferred embodiment, the ratio is about 10:2 to about 10:6. In an especially preferred embodiment, the ratio is about 10:4.
- Contemplated ratios include any value, subrange, or range within any of the recited ranges, including endpoints.
- the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH between about 4 and about 8. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 4. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 5. In one embodiment, the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 6.
- the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 7.
- the carrie carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH of about 8.
- the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are contacted with the binding agent in a solution having a pH between about 5 and about 7.
- the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are incubated with the binding agent at a temperature of about 5 °C to about 60 °C, or any range, subrange, or value within that range including endpoints.
- the carrier protein-paclitaxel (or paclitaxel derivative) nanoparticles are incubated with the binding agent at a temperature of about 23 °C to about 60 °C.
- the stability of the nanoparticle complexes is, at least in part, dependent upon the temperature and/or pH at which the nanoparticles are formed, as well as the concentration of the components (i.e., carrier protein, binding agent, paclitaxel or paclitaxel derivative, and a therapeutic agent) in the solution.
- the K4 of the nanoparticles is between about 1 x 10 "11 M and about 2 x 10 "5 M.
- the 3 ⁇ 4 of the nanoparticles is between about 1 x 10 "11 M and about 2 x 10 ⁇ 8 M.
- the K d of the nanoparticles is between about 1 x 10 "11 M and about 7 x 10 "9 M. In a preferred embodiment, the K d of the nanoparticles is between about 1 x 10 "11 M and about 3 x 10 "8 M. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints.
- the relative weight ratio of the carrier protein to the paclitaxel is greater than about 9: 1.
- the carrier protein and the paclitaxel have a relative weight ratios of greater than about 10: 1, or about 11 : 1, or about 12: 1, or about 13 : 1, or about 14: 1, or about 15: 1, or about 16: 1, or about 17: 1, or about 18: 1, or about 19: 1, or about 20: 1, or about 21 : 1, or about 22: 1, or about 23 : 1, or about 24: 1, or about 25: 1, or about 26: 1, or about 27: 1, or about 28: 1, or about 29: 1, or about 30: 1.
- the weight ratio is between 10: 1 and 100: 1, between 10: 1 and 50: 1, between 10: 1 and 40: 1, between 10: 1 and 30: 1, between 10: 1 and 20: 1, or between 10: 1 and 15: 1. In one embodiment, the weight ratio is between 15: 1 and 50: 1, 15: 1 and 50: 1, between 15: 1 and 40: 1, between 15: 1 and 30: 1, or between 15: 1 and 20: 1.
- the weight ratio may be any value or subrange within the recited ranges, including endpoints.
- the amount of paclitaxel is equal to a minimum amount capable of providing stability to the nanoparticles. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier. For example, less than about 1 mg of taxol can be added 9 mg of carrier protein (10 mg carrier protein-therapeutic) and 4 mg of binding agent, e.g., antibody, Fc fusion molecule, or aptamer, in 1 mL of solution.
- binding agent e.g., antibody, Fc fusion molecule, or aptamer
- the amount of paclitaxel present in the nanoparticle composition is less than about 5 mg/mL. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is less than about 4.54 mg/mL, or about 4.16 mg/mL, or about 3.57 mg/mL, or about 3.33 mg/mL, or about 3.12 mg/mL, or about 2.94 mg/mL, or about 2.78 mg/mL, or about 2.63 mg/mL, or about 2.5 mg/mL, or about 2.38 mg/mL, or about 2.27 mg/mL, or about 2.17 mg/mL, or about 2.08 mg/mL, or about 2 mg/mL, or about 1.92 mg/mL, or about 1.85 mg/mL, or about 1.78 mg/mL, or about 1.72 mg/mL, or about 1.67 mg/mL. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of providing
- the amount of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of providing affinity of the at least one therapeutic agent to the protein carrier. In one embodiment, the amount of paclitaxel present in the nanoparticle composition is greater than or equal to a minimum amount capable of facilitating complex formation of the at least one therapeutic agent and the protein carrier.
- the nanoparticle compositions described herein includes no binding agents.
- Exposed charges allow for charge- charge interactions between the two proteins which can alter the binding affinity of each protein to the other.
- concentration of the nanoparticles increases significantly as the solvent (e.g., water) is removed. Such increased concentrations of nanoparticles could lead to irreversible oligomerization.
- Oligomerization is a known property of proteins that reduces the biological properties of the oligomer as compared to the monomeric form and increases the size of the particle sometimes beyond 1 micron.
- a stable form of a nanoparticle composition is required for clinical and/or commercial use where a shelf-life of at least 3 months is required and shelf-lives of greater than 6 months or 9 months are preferred.
- Such a stable composition must be readily available for intravenous injection, must retain its self-assembled form upon intravenous injection so as to direct the nanoparticle to the predetermined site in vivo, must have a maximum size of less than 1 micron so as to avoid any ischemic event when delivered into the blood stream, and finally must be compatible with the aqueous composition used for injection.
- Lyophilization removes water from a composition.
- the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment.
- An excipient may be included in pre-lyophilized formulations to enhance stability during the freeze-drying process and/or to improve stability of the lyophilized product upon storage. Pikal, M. Biopharm. 3(9)26-30 (1990) and Arakawa et al., Pharm. Res. 8(3):285- 291 (1991).
- proteins may be lyophilized, the process of lyophilization and reconstitution may affect the properties of the protein. Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems. For a protein to remain biologically active, a formulation must preserve intact the conformational integrity of at least a core sequence of the protein's amino acids while at the same time protecting the protein's multiple functional groups from degradation. Degradation pathways for proteins can involve chemical instability (i.e. any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (i.e. changes in the higher order structure of the protein).
- chemical instability i.e. any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity
- physical instability i.e. changes in the higher order structure of the protein.
- the lyophilized compositions of this invention are prepared by standard lyophilization techniques with or without the presence of stabilizers, buffers, etc. Surprisingly, these conditions do not alter the relatively fragile structure of the nanoparticles. Moreover, at best, these nanoparticles retain their size distribution upon lyophilization and, more importantly, can be reconstituted for in vivo administration (e.g., intravenous delivery) in substantially the same form and ratios as if freshly made.
- the nanoparticles are lyophilized.
- the nanoparticle complexes e.g., RTP or NTP with associated therapeutic agent and/or binding agents
- the nanoparticle complexes upon reconstitution with an aqueous solution, an amount of the binding agents are arranged on a surface of the nanoparticles.
- the nanoparticle complexes upon reconstitution with an aqueous solution, an amount of the binding agents are arranged on a surface of the nanoparticles.
- the nanoparticle complexes are capable of binding to an antigen.
- the antibodies associated with the nanoparticle complexes remain capable of binding to the antigen.
- the nanoparticle composition is formulated for systemic delivery, e.g., intravenous administration.
- the nanoparticle composition is formulated for direct injection into a tumor.
- Direct injection includes injection into or proximal to a tumor site, perfusion into a tumor, and the like. Because the nanoparticle composition is not administered systemically, a nanoparticle composition is formulated for direct injection into a tumor may comprise any average particle size. Without being bound by theory, it is believed that larger particles (e.g., greater than 500 nm, greater than 1 ⁇ , and the like) are more likely to be immobilized within the tumor, thereby providing what is believed to be a better beneficial effect.
- composition comprising a compound provided herein, and at least one pharmaceutically acceptable excipient.
- the compounds provided herein can be formulated for administration to a patient by any of the accepted modes of administration.
- Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., ed. (1995) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.
- compounds provided herein will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
- routes oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
- compositions are comprised of, in general, a compound of the present invention in combination with at least one pharmaceutically acceptable excipient.
- Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
- excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
- Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
- Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
- Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
- Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
- compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
- a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials.
- the pack or dispenser device may be accompanied by instructions for administration.
- Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Treatment Methods
- nanoparticle compositions as described herein are useful in treating cancer cells and/or tumors in a mammal.
- the mammal is a human (i.e., a human patient).
- a lyophilized nanoparticle composition is reconstituted
- a method for treating a cancer cell comprising contacting the cell with an effective amount of nanoparticle composition as described herein to treat the cancer cell.
- Treatment of a cancer cell includes, without limitation, reduction in proliferation, killing the cell, preventing metastasis of the cell, and the like.
- a method for treating a tumor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a nanoparticle composition as described herein to treat the tumor.
- the method comprises selecting a patient having a cancer which expresses the antigen.
- the size of the tumor is reduced.
- the tumor size does not increase (i.e. progress) for at least a period of time during and/or after treatment.
- the nanoparticle composition is administered intravenously. In one embodiment, the nanoparticle composition is administered directly to the tumor. In one embodiment, the nanoparticle composition is administered by direct injection or perfusion into the tumor.
- the method comprises:
- the therapeutically effective amount of the nanoparticles described herein comprises about 1 mg/m 2 to about 200 mg/m 2 antibody, about 2 mg/m 2 to about 150 mg/m 2 , about 5 mg/m 2 to about 100 mg/m 2 , about 10 mg/m 2 to about 85 mg/m 2 , about 15 mg/m 2 to about 75 mg/m 2 , about 20 mg/m 2 to about 65 mg/m 2 , about 25 mg/m 2 to about 55 mg/m 2 , about 30 mg/m 2 to about 45 mg/m 2 , or about 35 mg/m 2 to about 40 mg/m 2 antibody.
- the therapeutically effective amount comprises about 20 mg/m 2 to about 90 mg/m 2 antibody.
- the therapeutically effective amount comprises 30 mg/m 2 to about 70 mg/m 2 antibody.
- the therapeutically effective amount of the nanoparticles described herein comprises about 50 mg/m 2 to about 200 mg/m 2 carrier protein or carrier protein and therapeutic agent. In one embodiment, the therapeutically effective amount of the nanoparticle compositions described herein comprise no binding agents. In one embodiment, the therapeutically effective amount of the nanoparticle compositions described herein comprise less than about a therapeutically effective amount of paclitaxel. In a preferred embodiment, the therapeutically effective amount comprises about less than 75 mg/m 2 of paclitaxel. Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints.
- the therapeutically effective amount comprises about 20 mg/m 2 to about 90 mg/m 2 binding agent, e.g., antibody, aptamer or fusion protein. In a preferred embodiment, the therapeutically effective amount comprises 30 mg/m 2 to about 70 mg/m 2 binding agent, e.g., antibody, aptamer or fusion protein.
- Contemplated values include any value, subrange, or range within any of the recited ranges, including endpoints.
- Cancers or tumors that can be treated by the compositions and methods described herein include, but are not limited to the cancers referred to in the above tables, as well as: biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer, gastric cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer (hepatocarcinoma); lung cancer; lymphomas, including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer, including squamous cell carcinoma; ovarian cancer, including those arising from epithelial cells
- osteosarcoma skin cancer, including melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer; testicular cancer, including germinal tumors (seminoma, non- seminoma[teratomas, choriocarcinomas]), stromal tumors and germ cell tumors; thyroid cancer, including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor.
- cancers or tumors include breast cancer, lymphoma, multiple myeloma, and melanoma.
- the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
- the actual amount of the compound of this invention, i.e., the nanoparticles, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to the skilled artisan.
- an effective amount or a therapeutically effective amount or dose of an agent refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject.
- Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ED50. Agents that exhibit high therapeutic indices are preferred.
- the effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
- Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects; i.e., the minimal effective concentration (MEC).
- MEC minimal effective concentration
- the MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
- the treatment comprises administration of the targeting binding agent prior to administration of the nanoparticles.
- the targeting binding agent is administered between about 6 and 48, or 12 and 48 hours prior to
- the targeting binding agent is administered between 6 and 12 hours prior to administration of the nanoparticles. In yet another embodiment, the targeting binding agent is administered between 2 and 8 hours prior to administration of the nanoparticles. In still other embodiments, the targeting binding agent is administered a week prior to administration of the nanoparticles. For example,
- pretreatment with BEV may comprise administration of lmg/kg BEV which is 1/lOth the usual dose, followed by administration of the nanoparticles or nanoparticle complexes.
- nanoparticles composed of albumin-bound paclitaxel or paclitaxel derivative as a core, and bevacizumab (i.e., Avastin®) or Rituximab (i.e., Rituxan®) as antibodies.
- bevacizumab i.e., Avastin®
- Rituximab i.e., Rituxan®
- ADC antibody dependent chemotherapy
- PBS Phosphate buffered saline
- the solution was split into freeze drying flasks at appropriate volumes to allow full lyophilization of product. Flask with solution were placed at -80 °C for 2-4 hours. The frozen solution in the flasks were lyophilized using a bench top freeze dryer with condenser of -85 °C at ⁇ 20 mtorr.
- Example 1 To determine whether NTP and bevacizumab (BEV) interact, the size of the NTP formed in Example 1 was analyzed by Malvern Nanosight technology, alone and after incubatiuon with 4, 6, 8, and 10 miligrams per milliliter (mg/mL) of bevacizumab for 30 minutes.
- NTP Nanoparticles
- Binding affinity (K d ) of both bevacizumab (FIG. 3 A) and rituximab (FIG. 3B) to NTP was measured using Bio Layer Interferometry Technology. Both antibodies were
- NTP Non-Toxic Nanoparticles
- Antibody free NTP and ABRAXANE® (ABX) solutions were made to 30 ⁇ g/mL of Meerwein's Product of Paclitaxel and paclitaxel, respectively, in PBS.
- a baseline count of nanoparticles per mL was obtained using Malvern Nanosight technology. Then a range of dilutions was made for both solutions, and particle concentration was measured.
- FIG 4A shows the stability of ABX and NTP in saline. Abraxane nanoparticles began to fall apart around 1 : 1.33 dilution of initial solution until it reached the baseline PBS levels at -1 :2 dilution. NTP decreased linearly with dilution factor, suggesting no particle fall apart.
- FIG 4B shows the stability of ABX and NTP in serum.
- NTP and ABX solutions were made to 250 ⁇ g/mL of Meerwein's Product of Paclitaxel and paclitaxel, respectively, in serum.
- Initial concentrations of nanoparticles were measured using Malvern Nanosight Technology, subsequent measurements are presented as a percentage of initial concentration. Concentrations of each solution were measured after 15, 30, 45, and 60 minutes in serum.
- ABX, AR160, Non-toxic nanoparticle (NTP) and rituximab-bound NTP were prepared as described above or previously ⁇ see, e.g., PCT Pub. No. WO2014/055415, which is incorporated herein by reference in its entirety).
- the nanoparticles and unlabeled rituximab were co-incubated with CD20+ Daudi lymphoma cells for 30 minutes at room temperature. The cells were washed and subsequently stained with PE anti-human CD20. Isotype (FIG. 5A) and anti-CD20 (FIG. 5B) stained cells served as negative and positive controls, respectively.
- paclitaxel is dissolved in a solvent (e.g., methylene chloride; or chloroform and ethanol).
- a solvent e.g., methylene chloride; or chloroform and ethanol.
- the solution is added to 27.0 mL of human serum abumin solution (1% w/v).
- the mixture is homogenized for 5 minutes at low RPM in order to form a crude emulsion, and then transferred into a high pressure
- the emulsification is performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles.
- the resulting system is transferred into a rotary evaporator, and methylene chloride is rapidly removed at 40° C, at reduced pressure (30 mm Hg), for 20-30 minutes.
- the dispersion is filtered through a 0.22 micron filter.
- the filtered nanoparticles may be lyophilized and stored.
- Albumin-paclitaxel-therapeutic agent nanoparticles having reduced amounts of paclitaxel compared to ABRAXANE® are formed.
- albumin-paclitaxel nanoparticles are formed as described in Example 6.
- a therapeutic agent e.g., cisplatin
- Free therapeutic agent e.g., cisplatin
- HPLC HPLC in the supernatant after nanoparticle particulate is removed.
- Example 8 Albumin-Paclitaxel-Antibody Nanoparticles with Reduced Paclitaxel
- albumin-paclitaxel nanoparticles are formed as described in Example 6. Nanoparticles (10 mg) are combined with an antibody (e.g., bevacizumab) (4 mg), and 840 ⁇ of 0.9% saline is added to give a final concentration of 10 mg/ml and 2 mg/ml of
- an antibody-albumin-paclitaxel-therapeutic agent nanoparticle complex may be formed.
- antibody is incubated with albumin-paclitaxel-therapeutic agent nanoparticles (from Example 7) to form antibody-albumin-paclitaxel-therapeutic agent nanoparticle complexes.
- the antibody-albumin-paclitaxel nanoparticles my beincubated with the therapeutic agent to form antibody-albumin-paclitaxel-therapeutic agent nanoparticle complexes.
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AU2017324947A AU2017324947A1 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
KR1020237000204A KR20230010817A (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
KR1020197009303A KR102486055B1 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binder compositions and methods of use and preparation thereof |
US16/328,146 US11311631B2 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
RU2019110070A RU2756892C2 (en) | 2016-09-06 | 2017-09-06 | Compositions with paclitaxel, albumin and binding agent and methods for their use and preparation |
JP2019512649A JP7025412B2 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binder composition and method of use and production of the composition |
CA3035653A CA3035653A1 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
CN201780066304.XA CN109890422A (en) | 2016-09-06 | 2017-09-06 | Taxol-albumin-binding agent composition and the method for using and preparing the composition |
EP17772158.6A EP3509643A1 (en) | 2016-09-06 | 2017-09-06 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
JP2022019316A JP2022065061A (en) | 2016-09-06 | 2022-02-10 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
US17/695,230 US20220211870A1 (en) | 2016-09-06 | 2022-03-15 | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
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